Bevacizumab-containing Therapy Research Articles

Hypertension as predictive factor for bevacizumab-containing first-line therapy in metastatic breast and colorectal cancer in BRECOL (GEICAM/2011-04) study

BackgroundRetrospective data suggest an association between bevacizumab efficacy and the incidence of arterial hypertension (AHT). Additionally, epigenetic mechanisms have been related to AHT.MethodsThis prospective observational study conducted by GEICAM Spanish Breast Cancer Research Group included metastatic breast (MBC) or colorectal (mCRC) cancer patients treated with bevacizumab-containing chemotherapy as first-line treatment. Blood pressure (BP) levels were measured (conventional and 24-h Holter monitoring) at baseline and up to cycle 3. Primary endpoint assessed BP levels increase as predictive factor for progression-free survival (PFS). Germline DNA methylation profile was explored in pre-treatment blood samples; principal component analysis was used to define an epigenetic predictive score for increased BP levels.ResultsFrom Oct-2012 to Jul-2016, 143 (78 MBC and 65 mCRC) patients were included. The incidence of AHT according to guidelines was neither predictive of PFS nor of best overall tumor response (BOR). No statistically significant association was observed with systolic BP nor diastolic BP increment for PFS or BOR. Grade 3 and 4 adverse events were observed in 37 and 5% of patients, respectively. We identified 27 sites which baseline methylation status was significantly associated to BP levels increase secondary to bevacizumab-containing chemotherapy.ConclusionsNeither the frequency of AHT nor the increase of BP levels were predictive of efficacy in MBC and mCRC patients treated with bevacizumab-containing chemotherapy.Clinical trial registryClinicalTrials.gov Identifier: NCT01733628.

A prognostic model for overall survival in recurrent glioma patients treated with bevacizumab-containing therapy

Predictive markers and prognostic models are useful for the individualization of cancer treatment. In this study, we sought to identify clinical and molecular factors to predict overall survival in recurrent glioma patients receiving bevacizumab-containing regimens. A cohort of 102 patients was retrospectively collected from June 2011 to January 2022 at our institution. A nomogram was generated by Cox regression and feature selection algorithms based on 19 clinicopathological and 60 molecular variables. The model's performance was internally evaluated by bootstrapping in terms of discrimination and calibration. The median overall survival from the initiation of bevacizumab administration to death or last follow-up was 11.6 months (95% CI: 9.2–13.8 months) for all 102 patients, 10.2 months (95% CI: 6.4–13.3 months) for 66 patients with grade 4 tumors, and 13.8 months (lower limit of 95% CI: 11.5 months) for 36 patients with tumors of grade lower or not available. In the final model, a lower WHO 2021 grade (Grade lower or not available vs. Grade 4, HR: 0.398, 95% CI: 0.223–0.708, p = 0.00172), having received adjuvant radiochemotherapy (Yes vs. No, HR: 0.488, 95% CI: 0.268–0.888, p = 0.0189), and wildtype EGFR (Wildtype vs. Altered, HR: 0.193, 95% CI: 0.0506–0.733, p = 0.0157; Not available vs. Altered, HR: 0.386, 95% CI: 0.184–0.810, p = 0.0118) were significantly associated with longer overall survival in multivariate Cox regression. The overall concordance index was 0.652 (95% CI: 0.566–0.714), and the areas under the time-dependent curves for 6-, 12-, and 18-month overall survival were 0.677 (95% CI: 0.516–0.816), 0.654 (95% CI: 0.470–0.823), and 0.675 (95% CI: 0.491–0.860), respectively. A prognostic model for overall survival in recurrent glioma patients treated with bevacizumab-based therapy was established and internally validated. It could serve as a reference tool for clinicians to assess the extent the patients may benefit from bevacizumab and stratify their treatment response.

Early evaluation of liver metastasis using spectral CT to predict outcome in patients with colorectal cancer treated with FOLFOXIRI and bevacizumab

PurposeEarly evaluation of the efficacy of first-line chemotherapy combined with bevacizumab in patients with colorectal cancer liver metastasis (CRLM) remains challenging. This study used 2-month post-chemotherapy spectral computed tomography (CT) to predict the overall survival (OS) and response of CRLM patients with bevacizumab-containing therapy.MethodThis retrospective analysis was performed in 104 patients with pathologically confirmed CRLM between April 2017 and October 2021. Patients were treated with 5-fluorouracil, leucovorin, oxaliplatin or irinotecan with bevacizumab. Portal venous phase spectral CT was performed on the target liver lesion within 2 months of commencing chemotherapy to demonstrate the iodine concentration (IoD) of the target liver lesion. The patients were classified as responders (R +) or non-responders (R −) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at 6 months. Multivariate analysis was performed to determine the relationships of the spectral CT parameters, tumor markers, morphology of target lesions with OS and response. The differences in portal venous phase spectral CT parameters between the R + and R − groups were analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the predictive power of spectral CT parameters.ResultsOf the 104 patients (mean age ± standard deviation: 57.73 years ± 12.56; 60 men) evaluated, 28 (26.9%) were classified as R + . Cox multivariate analysis identified the iodine concentration (hazard ratio [HR]: 1.238; 95% confidence interval [95% CI]: 1.089–1.408; P < 0.001), baseline tumor longest diameter (BLD) (HR: 1.022; 95% CI: 1.005–1.038, P = 0.010), higher baseline CEA (HR: 1.670; 95% CI: 1.016–2.745, P = 0.043), K-RAS mutation (HR: 2.027; 95% CI: 1.192–3.449; P = 0.009), and metachronous liver metastasis (HR: 1.877; 95% CI: 1.179–2.988; P = 0.008) as independent risk factors for patient OS. Logistic multivariate analysis identified the IoD (Odds Ratio [OR]: 2.243; 95% CI: 1.405–4.098; P = 0.002) and clinical N stage of the primary tumor (OR: 4.998; 95% CI: 1.210–25.345; P = 0.035) as independent predictor of R + . Using IoD cutoff values of 4.75 (100ug/cm3) the area under the ROC curve was 0.916, sensitivity and specificity were 80.3% and 96.4%, respectively.ConclusionsSpectral CT IoD can predict the OS and response of patients with CRLM after 2 months of treatment with bevacizumab-containing therapy.

541P Efficacy of various anticancer agents after failure of maintenance olaparib: A retrospective study

maintenance therapy with PARP-inhibitors (PARPi) may alter efficacy of further chemotherapy in advanced epithelial ovarian cancer (aEOC). We conducted a retrospective study to evaluate efficacy of various therapeutic agents in aEOC patients who progressed after maintenance olaparib therapy. we extracted data for patients with BRCA-positive aEOC who progressed after maintenance olaparib therapy from a prospectively maintained institutional database for 2014-2022 years. Using Cox proportional hazards regression model we analyzed the impact of various platinum, non-platinum and antiangiogenic agents on progression-free survival (PFS) and overall survival (OS) of patients after subsequent anticancer therapy. Statistical analysis was done with R and RStudio software. we identified 146 patients who received maintenance olaparib in the specified timeline, of them 61 (41.7%) patients were treated with subsequent chemotherapy and had available outcomes data. Median duration of previous olaparib therapy was 11.5 mo., the drug was administered as maintenance therapy after median of 2 (1-7) lines of anticancer treatment. Median follow-up time post olaparib progression was 13.0 months. Median post progression PFS and OS were 7.2 mo. and 20.0 mo. Results of Cox-regression analysis of PFS and OS are summarized in Table below. Taxanes- and/or bevacizumab-containing therapy was associated with better outcomes compared to other therapeutic options. Administration of anthracyclines (PLD or doxorubicin) had a detrimental impact on PFS and OS.Table: 541PFactorPFSOSHR (95% CI)pHR (95% CI)p>2 prior lines.97 (.54-1.76).345.48 (.19-1.21).124Taxanes0.47 (.25-.86).0140.26 (.07-.89).032Anthracyclines5.7 (2.48-13.12)<.001*2.57 (1.02-6.51).045Gemcitabine1.28 (.64-2.56).4691.15 (.37-3.53).797Pt-agents1.28 (.56-2.91).546.75 (.24-2.31).627Bevacizumab.54 (0.29-0.98).043.46 (.17-1.20).114*remained significant in multifactor analysis. Open table in a new tab *remained significant in multifactor analysis. taxanes and bevacizumab are valuable therapeutic options for post-olaparib treatment. Anthracyclines may be associated with inferior outcomes in this setting. While optimal treatment for patients progressing after PARPi is unknown, our study provides some insights and hypothesis-generating data for further trials.

Efficacy and safety of bevacizumab-containing therapy for refractory advanced breast cancer: a retrospective study.

Advanced breast cancer (ABC) is difficult to treat due to the primary and acquired resistance, which is the main cause of rescue treatment failure. Thus, developing a new rescue treatment strategy for clinicians is a challenge. This study retrospectively collected the medical information of patients with refractory ABC who were treated with bevacizumab at our department to analyze the efficacy and safety of bevacizumab-containing therapy as a new treatment method for refractory ABC. The complete medical information of patients receiving bevacizumab treatment from November 2017 to November 2020 was collected, and patients' general medical history and disease characteristics were analyzed. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to failure (TTF), overall survival (OS), and safety were also analyzed using SPSS 20.0 statistical software. The data of 68 women with refractory ABC who received bevacizumab-containing therapy were collected. The last follow-up examinations were performed on March 31, 2021. The ORR was 41.2% and the DCR was 88.2%. The median PFS, TTF, and OS were 6.0 months [95% confidence interval (CI): 3.4-8.6 months], 4.0 months (95% CI: 3.2-4.8 months), and 26.6 months (95% CI: 10.2-43.0 months), respectively. Treatment was discontinued in 2 patients due to chemo-related adverse reactions. The main adverse events related to bevacizumab were hypertension (7.4%) and bleeding (2 cases, 2.9%), both of which were grade 1. No specific adverse events causing the discontinuation of bevacizumab treatment were observed in the other patients. Among patients with refractory ABC, bevacizumab-containing therapy is feasible and safe, and can be used as a new treatment strategy. However, the question of who can benefit the most from bevacizumab-containing therapy requires further exploration.

Bevacizumab Combined with Platinum–Taxane Chemotherapy as First-Line Treatment for Advanced Ovarian Cancer: Results of the NOGGO Non-Interventional Study (OTILIA) in 824 Patients

Simple SummaryThe OTILIA non-interventional study aimed to assess the safety and effectiveness of a standard treatment regimen for advanced ovarian cancer in Germany. All of the women participating in the study received chemotherapy combined with a targeted treatment called bevacizumab. Among the 824 women who received treatment in this study, the median duration of progression-free survival (time alive without their disease returning) was 19.4 months. This is similar to the results in previous randomized phase 3 trials in more restricted populations of women. The safety and effectiveness of treatment seemed to be similar in older (at least 70 years) and younger (less than 70 years) women. Quality of life improved over time.In the single-arm non-interventional OTILIA study, patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IIIB–IV ovarian cancer received bevacizumab (15 mg/kg every 3 weeks for up to 15 months) and standard carboplatin–paclitaxel. The primary aim was to assess safety and progression-free survival (PFS). Subgroup analyses according to age were prespecified. The analysis population included 824 patients (453 aged <70 years, 371 aged ≥70 years). At data cutoff, the median bevacizumab duration was 13.8 months. Grade ≥3 adverse events (AEs), serious AEs, and AEs leading to bevacizumab discontinuation were more common in older than younger patients, whereas treatment-related AEs were less common. Median PFS was 19.4 months, with no clear difference according to age (20.0 vs. 19.3 months in patients <70 vs. ≥70 years, respectively). One-year OS rates were 92% and 90%, respectively. Mean change from baseline in global health status/quality of life showed a clinically meaningful increase over time. In German routine oncology practice, PFS and safety were similar to reported randomized phase 3 bevacizumab trials in more selected populations. There was no notable reduction in effectiveness and tolerability in patients aged ≥70 years; age alone should not preclude use of bevacizumab-containing therapy. ClinicalTrials.gov: NCT01697488.

Real-World Experience of Bevacizumab as First-Line Treatment for Ovarian Cancer: The GINECO ENCOURAGE Cohort of 468 French Patients.

Introduction: Bevacizumab-containing therapy is considered a standard-of-care front-line option for stage IIIB–IV ovarian cancer based on results of randomized phase 3 trials. The multicenter non-interventional ENCOURAGE prospective cohort study assessed treatment administration and outcomes in the French real-world setting.Patients and Methods: Eligible patients were aged ≥ 18 years with planned bevacizumab-containing therapy for newly diagnosed ovarian cancer. The primary objective was to assess the safety profile of front-line bevacizumab in routine clinical practice; secondary objectives were to describe patient characteristics, indications/contraindications for bevacizumab, treatment regimens and co-medications, follow-up and monitoring, progression-free survival, and treatment at recurrence. In this non-interventional study, treatment was administered as chosen by the investigator and participation in the trial had no influence on the management of the disease.Results: Of 1,290 patients screened between April 2013 and February 2015, 468 were eligible. Most patients (86%) received bevacizumab 15 mg/kg every 3 weeks or equivalent, typically with carboplatin (99%) and paclitaxel (98%). The median duration of bevacizumab was 12.2 (range 0–28, interquartile range 6.9–14.9) months; 8% of patients discontinued bevacizumab because of toxicity. The most common adverse events were hypertension (38% of patients), fatigue (35%), and bleeding (32%). There were no treatment-related deaths. Most physicians (90%) reported blood pressure measurement immediately before each bevacizumab infusion and almost all (97%) reported monitoring for proteinuria before each bevacizumab infusion. Median progression-free survival was 17.4 (95% CI, 16.4–19.1) months. The 3-year overall survival rate was 62% (95% CI, 58–67%). The most commonly administered chemotherapies at recurrence were carboplatin and pegylated liposomal doxorubicin.Discussion: Clinical outcomes and tolerability with bevacizumab in this real-life setting are consistent with randomized trial results, notwithstanding differences in the treated patient population and treatment schedule.Clinical Trial Registration:ClinicalTrials.gov, Identifier NCT01832415.

Thromboembolic events and antithrombotic prophylaxis in advanced ovarian cancer patients treated with bevacizumab: secondary analysis of the phase IV MITO-16A/MaNGO-OV2A trial

IntroductionThe use of routine antithrombotic prophylaxis is not recommended for advanced cancer patients receiving chemotherapy. The effect of bevacizumab-containing therapy on the risk of thromboembolic events remains controversial in ovarian...

First-line bevacizumab-containing therapy for HER2-negative locally advanced/metastatic breast cancer: Real-world experience from >2000 patients treated in the multicentre AVANTI study

AimThe multicentre non-interventional AVANTI study assessed safety, effectiveness and patient-reported outcomes with approved first-line bevacizumab-containing regimens for HER2-negative locally recurrent/metastatic breast cancer (LR/MBC) in German routine oncology practice. MethodsEligible patients had HER2-negative LR/MBC, no bevacizumab contraindications and no prior chemotherapy for LR/MBC. Chemotherapy schedule, diagnostics and follow-up were at physicians’ discretion. Data were collected for 1 year after starting bevacizumab, then every 6 months for 1.5 years (maximum follow-up: 2.5 years). Patients and physicians rated treatment satisfaction. Subgroup analyses were prespecified in clinically relevant populations, including triple-negative breast cancer (TNBC). ResultsBetween November 1, 2009 and April 30, 2016, 2065 eligible patients at 346 centres received bevacizumab with paclitaxel or capecitabine. Patients receiving bevacizumab–capecitabine were less likely to have de novo disease and more likely to have TNBC, age ≥60 years and prior anthracycline/taxane and/or endocrine therapy. Median PFS was 12.6 (95% CI 11.9–13.2) months (12.8 with bevacizumab–paclitaxel, 10.5 with bevacizumab–capecitabine); median OS was 23.9 (95% CI 22.2–25.1) months. Outcomes were worse in patients with TNBC, prior anthracycline/taxane or prior endocrine therapy. Grade ≥3 adverse events occurred in 27% of patients. Treatment was discontinued for adverse events in 15%. Treatment satisfaction was rated as good or better by 304/394 responding patients (77%) at week 54 and in 1393/2065 patients (67%) by physicians overall. ConclusionsIn routine clinical practice, effectiveness and safety of first-line bevacizumab-containing therapy for LR/MBC were consistent with experience from phase III trials. Patient and physician treatment satisfaction showed high concordance.

Patient-reported outcomes in the randomized phase III IMagyn050/GOG3015/ENGOT-ov39 trial evaluating atezolizumab (atezo) with carboplatin/paclitaxel/bevacizumab for newly diagnosed ovarian cancer

<h3>Objectives:</h3> Although primary results from the IMagyn050 trial showed no statistically significant improvement in progression-free survival (PFS) with atezo added to carboplatin/paclitaxel/bevacizumab (CPB) [Moore, ESMO 2020], the impact of this regimen on selected patient (pt)-reported ovarian cancer symptoms, function, and health-related quality of life (HRQoL) is unknown and the focus of this study. <h3>Methods:</h3> IMagyn050 is a double-blind randomized phase 3 trial evaluating the efficacy and safety of adding atezo/placebo to CPB followed by maintenance bevacizumab + atezo/placebo. The trial includes two cohorts: neoadjuvant chemotherapy (NACT) and primary surgery (PS). Pts complete EORTC QLQ-C30, QLQ-OV28, and FACT-G single-item GP5 at baseline (BL) and at regular intervals during treatment and follow-up. In NACT pts, prespecified responder analyses (using a ≥10-point cutoff for clinically meaningful change) assessed improvement in abdominal pain (OV28 item 31) and bloating (OV28 item 32) at week 9, comparing treatment arms by Cochran-Mantel-Haenszel (CMH) testing. Additional secondary objectives in the NACT and PS cohorts were assessments of function (physical, role, emotional, social) and HRQoL, as measured by QLQ-C30 functional and global health status/quality of life scales. Exploratory endpoints included mean change from BL in symptoms (QLQ-C30 and OV28) and treatment side-effect bother (FACT-G GP5) in both cohorts. <h3>Results:</h3> Of 1301 randomized pts, completion rates for each of the 3 questionnaires were 83-100% at BL and >85% on treatment. In NACT pts, mean BL scores were similar in the atezo vs placebo arms for abdominal pain (40.2 vs 44.8) and bloating (50.4 vs 56.3). At week 9, there was no difference between treatments in the proportion of NACT pts with ≥10-point improvement in either symptom (abdominal pain: 69/136 [51%] with atezo vs 77/142 [54%] with placebo, CMH p=0.56; bloating: 74 [54%] vs 89 [63%], CMH p=0.14). Results were consistent when restricted to NACT pts with sufficient BL symptoms to show ≥10-point improvement. There was no difference between treatments in the proportion of NACT pts with improvement in function or HRQoL at week 9. In the PS cohort, similar proportions of pts in each arm showed on-treatment improvement, stabilization, or deterioration in function and HRQoL. In both cohorts, neither arm showed meaningful changes from BL in treatment-related symptoms and similar proportions of pts in both arms reported being ‘a little bit' or ‘somewhat' bothered by treatment side effects while on therapy. <h3>Conclusions:</h3> Consistent with PFS results, there were no differences between arms in the proportion of NACT pts with a clinically meaningful improvement in abdominal pain and bloating after 3 cycles of bevacizumab-containing therapy. Pt-reported outcome analyses in both cohorts showed that adding atezo to CPB did not increase treatment burden for pts, thereby demonstrating the tolerability of this 4-drug regimen and providing further insight on the benefit-risk assessment of atezo.

Identifying response in colorectal liver metastases treated with bevacizumab: development of RECIST by combining contrast-enhanced and diffusion-weighted MRI.

Response evaluation criteria in solid tumors (RECIST) often fail to identify clinically meaningful response to bevacizumab-containing therapy in colorectal liver metastasis (CRLM). This study aimed to develop RECIST by combining contrast-enhanced and diffusion-weighted magnetic resonance imaging (MRI). A total of 126 patients with CRLM who underwent hepatic resection after bevacizumab-containing chemotherapy were split into initial analyses cohort (N = 42, with 76 indexed liver metastases) and validation cohort (N = 84). In lesion-based analyses, percentage decrease of arterial enhancement area and percentage increase of apparent diffusion coefficient (ADC) value from baseline to post-chemotherapy were measured. Their optimal cutoff values for distinguishing pathology-confirmed major and minor response were determined. Then, the developed RECIST (D-RECIST) was established by combining functional and size-based items. Survival relevance of D-RECIST and RECIST was examined in the validation cohort. Percentage decrease of arterial enhancement area and increase of ADC value significantly differed between lesions of pathologic major or minor response, with optimal cutoffs of approximately 33% and 19%, respectively. Patients defined as responders by D-RECIST had a significantly longer median disease-free survival (DFS) than non-responders (p = 0.021; 12.9 versus 8.6 months). No significant difference was observed with RECIST (p = 0.524). In a Cox regression model, D-RECIST- but not RECIST-defined responses independently predicted the DFS (p = 0.034 and 0.811). D-RECIST-defined responses provided significant prognostic information, and thus may serve as a better response evaluation approach than RECIST in CRLM treated with bevacizumab-containing therapy. • Changes in arterial enhancement area and apparent diffusion coefficient value are associated with pathological response in colorectal liver metastases treated with bevacizumab. • The MRI-based response criteria developed by combining size-based and functional features can provide significant prognostic information.

Low Expression of miR-20a-5p Predicts Benefit to Bevacizumab in Metastatic Breast Cancer Patients Treated within the TANIA Phase III Trial.

Background: In metastatic breast cancer (MBC) patients, no biomarker predicting benefit to a bevacizumab-containing therapy has been established yet. MicroRNAs (miRNAs) are involved in angiogenesis and treatment resistance and therefore could be of predictive value. Methods: Profiling of 754 miRNAs was performed in tumor samples of 58 MBC patients treated with a bevacizumab-containing first-line regimen (learning set). Based on progression-free survival (PFS), patients were divided into responders (R) and non-responders (NR). Differentially expressed miRNAs between R and NR were analyzed in a cohort of 57 patients treated with first-line chemotherapy without bevacizumab (control set), to exclude miRNAs providing prognostic information. MiRNA candidates significantly associated with PFS in multivariate analysis were further validated in tumor samples of 203 patients treated within the phase III trial TANIA randomizing between chemotherapy either alone or with bevacizumab after progression on first-line bevacizumab. Results: Low expression of miR-20a-5p (multivariate p = 0.035) and miR-21-5p (multivariate p = 0.004) were significantly associated with longer PFS in the learning set, but not in the control set. In samples from the TANIA trial, low expression of miR-20a-5p was also significantly associated with longer PFS (hazard ration (HR) 0.60; 95%-CI 0.37–0.89; p = 0.012) and longer overall survival (OS; HR 0.54; 95%-CI 0.32–0.83; p = 0.007) in the bevacizumab arm but not in the chemotherapy-only arm (PFS: HR 0.73, p = 0.119; OS: HR 1.01; p = 0.964). For miR-21-5p no significant association with PFS or OS in both treatment arms was observed. Conclusion: MiR-20a-5p expression in breast cancer tissue was predictive for a greater benefit from bevacizumab-containing therapy in two independent cohorts.

Role of front-line bevacizumab in advanced ovarian cancer: the OSCAR study

ObjectiveTwo randomized phase III trials demonstrated the efficacy and safety of combining bevacizumab with front-line carboplatin/paclitaxel for advanced ovarian cancer. The OSCAR (NCT01863693) study assessed the impact of front-line bevacizumab-containing...

Efficacy of a Bispecific Antibody Co-Targeting VEGFA and Ang-2 in Combination with Chemotherapy in a Chemoresistant Colorectal Carcinoma Xenograft Model.

Vascular endothelial growth factor (VEGF) inhibition by the addition of bevacizumab to the chemotherapy regimen of metastatic colorectal cancer leads to an improved outcome. However, anti-angiogenic tumor therapy targeting a single factor may be limited by complementary mechanisms. Angiopoietin-2 (Ang-2, ANGPT2) is another important factor that cooperates with VEGF to drive tumor angiogenesis. It was shown that high Ang-2 levels are associated with a poor clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Therefore, combined inhibition of VEGF and Ang-2 was supposed to improve anti-angiogenic therapy. Here, we evaluated the efficacy of a bispecific antibody (CrossMab) co-targeting VEGF and Ang-2 in combination with chemotherapy in a chemoresistant colorectal carcinoma model. Antitumor activity was evaluated in athymic nude mice bearing subcutaneous DLD1 xenograft tumors and treated with anti-VEGF (B20), anti-Ang-2 (LC06) and anti-VEGF/Ang-2 (CrossMab) antibodies. Chemotherapy consisted of 5-FU and irinotecan. Resected tumors were analyzed immunohistochemically. First, an impact of targeting each single factor but also a clear advantage of co-targeting both factors could be demonstrated. Accordingly, tumor tissue showed strong staining for VEGF and Ang-2. Chemotherapy alone was less effective. Efficient tumor growth inhibition could be achieved by treatment with anti-VEGF/chemotherapy, single CrossMab and CrossMab/chemotherapy, which resulted in 3 out of 10, 6 out of 10 and 10 out of 10 complete responses, respectively, during seven weeks. Complete retarded tumors were characterized by massive intratumoral necrosis surrounded by layers of vital tumor cells and connective tissue with CD31-positive vessels at the periphery. In some cases, a distinct feature known as vessel co-option could be observed. In conclusion, the data from this model clearly support the strategy of co-targeting VEGF and Ang-2 and further demonstrate the beneficial impact of co-treatment with chemotherapy. The clear superiority of the CrossMab-containing regimen compared to clinical standard anti-VEGF/chemotherapy warrants further analyses in other models.

Abstract P3-10-07: A 3-gene DNA methylation signature fails to predict response to bevacizumab in metastatic breast cancer patients treated within the TANIA phase III trial

Abstract Background: Biomarkers predicting response to bevacizumab containing therapy in metastatic breast cancer (MBC) are of urgent need. In a retrospective single-institution analysis we have previously shown that a 3-gene methylation signature (MLH1,POLKand TMBIM6) could discriminate between responders and non-responders to a bevacizumab-based therapy in two independent cohorts of patients with MBC with an AUC of 0.94 and 0.86, respectively (Gampenrieder SP et al. Theranostics. 2018. 8(8):2278-2288). Here, we present the validation of these findings within the prospective phase III trial TANIA (Vrdoljak E et al. Ann Oncol. 2016. 27(11):2046-52) randomizing 494 patients with HER2-negative MBC to chemotherapy plus bevacizumab or chemotherapy alone for two consecutive treatment lines (second- and third-line). All patients had already received bevacizumab-containing therapy in the first-line setting. Patients and methods: DNA isolated from archival FFPE tumor samples was available from 200 patients consenting to optional translational research within the TANIA trial. Out of these, 176 samples were collected prior to first-line bevacizumab therapy and were analyzed retrospectively. Sufficient DNA for methylation analysis was available from 124 patients: 64 treated with chemotherapy plus bevacizumab and 60 treated with chemotherapy alone. All samples were isolated from the primary tumor. Quantitative methylation analysis was performed by pyrosequencing on the PyroMark Q24 Advanced System (Qiagen). PFS and OS analyses were performed in both study arms comparing “predicted responders” (PRED_R) versus “predicted non-responders” (PRED_NR) based either on median dichotomization or according to the cutoffs for individual CpG and the combined 3-CpG methylation logistic regression model. Results:Out of the 124 evaluable patients, 32 (25.8%) were classified as PRED_R and 92 as RED_NR by the 3-gene methylation signature. PRED_R did not have a significantly different second-line PFS (HR 0.95, 95%CI 0.57-1.57; P = 0.84) or OS (HR 0.91, 95%CI 0.51-1.60; P = 0.73) when treated in the bevacizumab-containing study arm compared to PRED_NR. In addition, PRED_R did not show a longer PFS when treated with bevacizumab compared to PRED_R treated with chemotherapy alone (HR 0.95, 95%CI 0.59-1.54; P = 0.83). Furthermore, there was no difference in third-line PFS and the combination of second- and third-line PFS between PRED_R and PRED-NR in the bevacizumab arm. In the control arm, PRED_NR showed a statistically significant shorter PFS compared to PRED_R (HR 0.50, 95%CI 0.22-0.77; P = 0.006), but not OS (HR 0.95, 95%CI 0.51-1.77; P = 0.86). Conclusion: Our 3-gene methylation signature was not confirmed as predictive biomarker for bevacizumab efficacy in metastatic breast cancer. (This research project was partially supported by ROCHE Austria GmbH) Citation Format: Gampenrieder SP, Angela R, Rinnerthaler G, Hackl H, Steiner M, Pulverer W, Weinhaeusel A, Klinglmayr E, Karl T, Ilic S, Hufnagl C, Hauser-Kronberger C, Egle A, Greil R. A 3-gene DNA methylation signature fails to predict response to bevacizumab in metastatic breast cancer patients treated within the TANIA phase III trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-07.

Real-world effectiveness of bevacizumab based on AURELIA in platinum-resistant recurrent ovarian cancer (REBECA): A Korean Gynecologic Oncology Group study (KGOG 3041)

PurposeTo evaluate the effectiveness of bevacizumab with single-agent chemotherapy for platinum-resistant ovarian cancer in a real-world setting. Patients and methodsWe enrolled recurrent platinum-resistant ovarian cancer patients from 27 institutions. All had received bevacizumab with single-agent chemotherapy (weekly paclitaxel, pegylated liposomal doxorubicin (PLD), topotecan) between 2015 and 2017 for second- or third-line chemotherapy in routine clinical practice. The primary endpoint was progression-free survival (PFS) and safety. Secondary endpoints included the objective response rate (ORR), PFS2, overall survival, duration of chemotherapy, and reasons for discontinuing chemotherapy. ResultsOf 391 patients, 259 (66.2%) received bevacizumab with PLD, 94 (24.0%) with topotecan, and 38 (9.7%) with weekly paclitaxel. The median PFS was 6.1 months with all forms of bevacizumab-containing therapy. Although the cohort with weekly paclitaxel had a better PFS than the PLD cohort (P = 0.028), this finding was not found in patients with a previous platinum-free interval of less than three months. The median duration of therapy was five cycles (range, one to 20 cycles), and 29 patients (7.4%) discontinued treatment because of adverse events from bevacizumab-containing regimens. The PLD cohort had fewer grade ≥ 3 adverse events than the other regimens (PLD, 35.8%; weekly paclitaxel, 52.6%; topotecan, 51.1%; P = 0.012), especially events of hematologic toxicities. ConclusionIn Korean ovarian cancer patients, the safety and effectiveness of chemotherapy with bevacizumab in a real-world setting was consistent with the results from a randomized controlled study. The effectiveness and toxicity profiles varied among the chemotherapy regimens, and this finding should be considered in practice.Clinical trials registration: NCT03367182.

99P - Micro-RNA profile in advanced metastatic breast cancer as a predictive tool for response to bevacizumab-paclitaxel

Background: Bevacizumab-containing therapy improves progression-free survival (PFS) in human epidermal growth factor receptor (HER) 2-negative metastatic breast cancer (mBC), but its use has been questioned due to the lack of benefit in overall survival (OS). To date, biomarkers to predict its positive effect are not available. Interestingly, miRNAs have emerged as regulators of most processes, forming tight interconnected feedback loops with genes under their regulation. Currently, different analyses, such as microarray, are performed in order to identify miRNA biomarkers, using formalin-fixed and paraffin-embedded (FFPE) tissue samples. Methods: In the present study we recorded clinical data from 57 mBC patients, and selected two (4 + 4) PFS extreme groups for the analysis of the miRnome. Three miRNAs were used for normalization (U6, 191-5p and 103-a-3p). miRNAs for model construction were selected by differential expression between the two groups. Candidates were measured in the remaining 49 cases, and stepwise based Akaike criterion was used for profile generation. Additionally, integrative miRNA and mRNA analyses were done to reveal markers and pathways with potential clinical impact. Results: We selected two groups of patients with extreme differences on PFS (2.48 ± 1.85 vs 35.43 ±8.03 months) for their miRnome study. The expression profiles of miRNAs in both groups were highly correlated, except for 13 miRNAs where statistical differences arised. These miRNAs were selected as candidates for profile generation on the 49 additional cases, and a combination of five of them (miR-362-3p, miR-150b-5p, miR-671-3p, miR-744-3p and miR-941) was able to accurately discriminate two PFS groups. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses on miRNA possible target genes revealed interesting pathways to explore in these patients, such as cellular adhesion. Conclusions: By combining experimental approaches and computational biology, we have identified candidate markers of outcome for bevacizumab-containing therapy. The five miRNAs included in the prognostic profile and cellular adhesion related genes should be explored as potential biomarkers. Legal entity responsible for the study: Fundación para la Investigación del Hospital Universitario La Paz Funding: None Disclosure: All authors have declared no conflicts of interest.

Comparative analysis of the effect of bevacizumab maintenance regimens after first-line chemotherapy in patients with metastatic colorectal cancer (MCRC): A single institution experience.

e15032 Background: The majority of patients with metastatic colorectal cancer (MCRC) will ultimately experience disease progression following initial therapy. Although phase III clinical trials show that continued maintenance therapy improves progression free and overall survival in MCRC, the optimal maintenance regimen with an acceptable safety profile is still undetermined. This study aimed to assess outcomes of bevacizumab-containing maintenance therapy after first line chemotherapy for MCRC. Methods: One hundred thirteen patients (46 males, 67 females) with MCRC diagnosed between 2005 and 2014 who received chemotherapy at Karmanos Cancer Institute were included in this retrospective analysis. Induction treatment for most patients consisted of either 5-FU or capecitabine-based chemotherapy with either oxaliplatin or irinotecan and with or without bevacizumab. Eighty percent of patients who received bevacizumab with induction also received it as part of maintenance therapy. Results: After stratifying for age (dichotomized at 65 years) and induction therapy bevacizumab, there was no difference in PFS for induction regimens with or without bevacizumab (p = 0.67). For patients who received capecitabine as maintenance chemotherapy, the addition of bevacizumab resulted in non-significant larger hazard of a PFS event (HR = 1.46, p = 0.36). Among those who received 5-FU maintenance, the addition of bevacizumab resulted in non-significant smaller hazard of a PFS event (HR = 0.48, p = 0.11). There was no difference in observed toxicities between patients who received bevacizumab and those who did not (p = 0.38), with further sub-set analysis showing no increased toxicities among those who received 5-FU (p = 0.76) and those who received capecitabine (p = 0.16). Conclusions: In patients with metastatic colorectal cancer, there was no difference in efficacy or safety when adding bevacizumab to either 5-FU or capecitabine for maintenance after first line chemotherapy. Based on our results, tolerability and compliance with oral capecitabine ought to be a key factor in determining the choice of maintenance in patients with MCRC.

Bevacizumab combined with chemotherapy for glioblastoma: a meta-analysis of randomized controlled trials.

Bevacizumab, as antibodies, were applied to inhibit tumor angiogenesis by preventing activation of vascular endothelial growth factor receptor. We analyzed four clinical trials, including 607 patients, to investigate the efficacy and safety of bevacizumab when combined with chemotherapy for the treatment of glioblastomas. Results demonstrated that bevacizumab when combined with chemotherapy improved progression-free survival (HR = 0.66; 95% CI 0.56–0.78; p < 0.00001) compared with bevacizumab or chemotherapy alone. Furthermore, overall survival showed insignificant difference between two arms (HR 0.99; 95% CI 0.8–1.21; p = 0.92). However, we found that patients treated with bevacizumab-containing therapy reported increased objective response rate (OR 1.85, 95% CI 1.17–2.93; p = 0.009), but more treatment-related adverse events (OR 1.75; 95% CI 1.09–2.83; p = 0.02).

Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer

The purpose of this analysis was to assess the long-term impact of adding bevacizumab to adjuvant chemotherapy for early triple-negative breast cancer (TNBC). Patients eligible for the open-label randomized phase III BEATRICE trial had centrally confirmed triple-negative operable primary invasive breast cancer (pT1a-pT3). Investigators selected anthracycline- and/or taxane-based chemotherapy for each patient. After definitive surgery, patients were randomized 1:1 to receive ≥4 cycles of chemotherapy alone or with 1 year of bevacizumab (5 mg/kg/week equivalent). Stratification factors were nodal status, selected chemotherapy, hormone receptor status, and type of surgery. The primary end point was invasive disease-free survival (IDFS; previously reported). Secondary outcome measures included overall survival (OS) and safety. After 56 months' median follow-up, 293 of 2591 randomized patients had died. There was no statistically significant difference in OS between treatment arms in either the total population (hazard ratio 0.93, 95% confidence interval [CI] 0.74-1.17; P = 0.52) or pre-specified subgroups. The 5-year OS rate was 88% (95% CI 86-90%) in both treatment arms. Updated IDFS results were consistent with the primary IDFS analysis. Five-year IDFS rates were 77% (95% CI 75-79%) with chemotherapy alone versus 80% (95% CI 77-82%) with bevacizumab. From 18 months after first study dose to study end, new grade ≥3 adverse events occurred in 4.6% and 4.5% of patients in the two arms, respectively. Final OS results showed no significant benefit from bevacizumab therapy for early TNBC. Late-onset toxicities were rare in both groups. Five-year OS and IDFS rates suggest that the prognosis for patients with TNBC is better than previously thought. NCT00528567.